TFCP2 and Alzheimer Disease

TFCP2 has been evaluated as a candidate susceptibility gene for Alzheimer disease, yet early replication studies in sizable French Caucasian cohorts have failed to confirm its association. These studies screened multiple candidates involved in key neurobiological pathways, but TFCP2 did not consistently emerge as a significant risk factor (PMID:19889475).

Genetic evidence for TFCP2 in Alzheimer disease remains limited. In one study comprising 428 cases and 475 controls, nominal associations observed for several genes were later deemed inconsistent upon further analysis (PMID:19889475), while a separate cluster analysis also did not validate a robust link with the disease (PMID:18307033). No familial segregation data with additional affected relatives have been reported.

A candidate variant, reported as an example in annotation lists, is c.123A>T (p.Lys41Asn). However, without corroborative segregation or replication studies, the variant’s clinical relevance in Alzheimer disease is unproven. The overall paucity of genetic evidence reduces confidence in TFCP2 as a major contributor to Alzheimer disease risk.

Conversely, multiple functional studies have elucidated aspects of TFCP2’s molecular role. Investigations demonstrate that TFCP2 participates in specific DNA-binding and dimerization processes that are essential for transcription regulation (PMID:8035790, PMID:16648487, PMID:19751393). Although these mechanistic data support the biological activity of TFCP2, they do not provide direct evidence linking its dysregulation to Alzheimer disease pathology.

In summary, the genetic association between TFCP2 and Alzheimer disease is disputed due to the failure of multiple replication studies to produce consistent results, whereas functional assays reveal relevant transcription factor properties that remain unlinked to disease causality. Additional evidence may exist but falls short of robust ClinGen scoring thresholds, and the conflicting findings necessitate caution when considering TFCP2 for diagnostic or therapeutic strategies.

Key Take‑home: Although TFCP2 exhibits important roles in transcriptional regulation, its clinical utility as an Alzheimer disease susceptibility marker is currently undermined by inconsistent replication of genetic associations.

References

• Neurobiology of aging • 2011 • No replication of genetic association between candidate polymorphisms and Alzheimer's disease PMID:19889475
• Neurochemical research • 2009 • Cluster analysis of risk factor genetic polymorphisms in Alzheimer's disease PMID:18307033
• Molecular and cellular biology • 1994 • One exon of the human LSF gene includes conserved regions involved in novel DNA-binding and dimerization motifs PMID:8035790
• Molecular and cellular biology • 2006 • Functional interaction of CP2 with GATA‑1 in the regulation of erythroid promoters PMID:16648487
• Genes to cells : devoted to molecular & cellular mechanisms • 2009 • Transactivation activity of LBP‑1 proteins and their dimerization in living cells PMID:19751393

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